Introducing dominant oncogenic alterations uncovered in human myeloid malignancies into the mouse germline provides a powerful approach for studying leukemogenesis. However, little is known about how gene inactivation contributes to the development of myeloid malignancies. We describe how Nf1 mutant mice provide one example in which disrupting a tumor suppressor gene has been used to generate an informative murine leukemia model. We also discuss how chromosome engineering technologies are being harnessed to model the segmental deletions found in myeloid malignancies, and how these approaches can be combined with retrovirally medicated insertional mutagenesis to generate new models and for gene discovery.